ZrCl2(η-C5Me5)2-AlHCl 2·(THF)2: Efficient hydroalumination of terminal alkynes and cross-coupling of the derived alanes

Article abstract of DOI:10.1039/c2cc37537k

Stabilized AlHCl₂·(THF)₂ hydroaluminates RCCH with exceptional chemo-, regio- and stereoselectivity under efficient ZrCl ₂(η-C₅Me₅)₂ catalysis (2-5 mol%). The resulting vinyl alanes undergo palladium cross-coupling with a wide range of sp² electrophiles (aryl, heteroaryl and vinyl halides/pseudohalides) in good to excellent yields. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2cc37537k

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ZrCl (g-C Me ) -AlHCl (THF) : efficient
2ꢀ
2
5
5 2
2
hydroalumination of terminal alkynes and
cross-coupling of the derived alanes†
Cite this: DOI: 10.1039/c2cc37537k
Received 16th October 2012,
Accepted 6th November 2012
Philip Andrews, Christopher M. Latham, Marc Magre, Darren Willcox and
Simon Woodward*
DOI: 10.1039/c2cc37537k
www.rsc.org/chemcomm
R
Stabilized AlHCl2ꢀ(THF)2 hydroaluminates RC CH with exceptional also known common issues. (v) The presence of bulky, poten-
chemo-, regio- and stereoselectivity under efficient ZrCl2(g-C5Me5)2 tially transferable, i-butyl groups in alanes 1 (R = Bui) is also
catalysis (2–5 mol%). The resulting vinyl alanes undergo palladium known to complicate or slow subsequent transmetallation to
cross-coupling with a wide range of sp2 electrophiles (aryl, hetero- modern selective catalysts when using such vinylalanes as
aryl and vinyl halides/pseudohalides) in good to excellent yields.
terminal C-nucleophiles in cascade approaches.
Because of the above limitations alternative hydrometalation
Despite the intrinsic usefulness of Zweifel’s HAlBui2 (DIBAL-H), strategies6 have been developed, often using B- and Zr-based
direct formation of a-vinylalanes 1 (Scheme 1, Y = Bui) by this reagents. Vinylboranes although easily prepared can be sensitive
reagent using terminal acetylenes is not without issues:1,2 (i) to hydrodeborination in subsequent couplings unless more
Neat DIBAL-H is significantly pyrophoric. (ii) Direct thermal expensive pinacol7 or MIDA-based8 reagents are used. Moreover,
reaction of RCRCH and DIBAL-H in heptane (Negishi’s pro- transmetallation or other activation of vinylboranes is typically
cedure3) is limited to R = alkyl as more electron withdrawing R required for such species. While stoichiometric use of the
groups lead to significant alkyne deprotonation (giving 2) not Schwartz reagent9 ZrHCl(Z-C5H5)2 with RCRCH does offer
hydroalumination. (iii) Attaining highly chemo- and regioselec- clean access to vinyl zircocenyl species, analogues of (E)-1, this
tive terminal alkyne hydroalumination under such conditions is at the cost of poor mass/atom economy.
can be challenging (i.e. formation of only (E)-1 without any 2 or
In seeking a route to (E)-1, where Y is a small, non transferable
(Z)-1, or 3). Sometimes relatively high terminal C(1) selectivity group, we considered dichloroalane (HAlCl2). Although there is no
can be attained through the use of catalysts,4 or by use of report of terminal alkyne hydroalumination10 with this reagent, its
RCRCTMS as a terminal alkyne surrogate.5 (iv) Alkyne over use is attractive as stabilized adducts11 (including some formed
reduction (leading to 4–5) and functional group intolerance are directly from AlCl3/Al powder and H2 at large scales12) are already
known. We could note that some of these can be handled for short
times in air (ca. 30 min) and thought the decreased reactivity of such
adducts might allow clean formation of (E)-1 without the complica-
tions of Scheme 1. Preliminary studies revealed HAlCl2ꢀ(THF)2
Table 1 Hydroalumination of 1-decyne by HAlCl2ꢀ(THF)2 (1.5 equiv.)a
Run Catalystb
Conversionc (%) (E)-1 : (Z)-1 : 2 : 3 : 4 : 5d
1
2
3
4
5
6
7
8
None
7
77
90 : 0 : 0 : 0 : 0 : 10
53 : 2 : 0 : 42 : 1 : 2
74 : 0 : 15 : 5 : 5 : 0
75 : 3 : 0 : 6 : 14 : 3e
87 : 0 : 1 : 2 : 7 : 3
85 : 0 : 0 : 2 : 11 : 2
82 : 0 : 0 : 2 : 15 : 2
75 : 0 : 0 : 3 : 18 : 3
Cp2TiCl2 (5 mol%)
Cp2ZrCl2 (5 mol%)
Cpꢁ2TiCl2 (5 mol%)
up to 51
>98
95
85
77
Cpꢁ2ZrCl2 (5 mol%)
Cpꢁ2ZrCl2 (2 mol%)
Cpꢁ2ZrCl2 (1 mol%)
Scheme 1 Desired (E)-1 and common by-products in hydroalumination of
RCRCH by HAlY2 (Y = Bui, Cl).
Cpꢁ2ZrCl2 (0.5 mol%) 71
School of Chemistry, The University of Nottingham, University Park, Nottingham,
UK. E-mail: simon.woodward@nottingham.ac.uk; Fax: +44 (0)115 9513564;
Tel: +44 (0)115 9513541
a
Chemistry of Scheme 1 (R = C8H17, Y = Cl) using 1-decyne (1.0 mmol)
b
c
in THF (1.4 mL) at 80 1C, 2 h. Cp is Z-C5H5, Cp* is Z-C5Me5. By
1H NMR spectroscopy of the crude product. By 2H{1H} NMR spectro-
d
e
† Electronic supplementary information (ESI) available: Experimental, spectro-
scopic, 2H{1H} NMR aquisition details. See DOI: 10.1039/c2cc37537k
scopy on D2O quenched reaction mixture. Minor additional unchar-
acterised components and d0-alkene also present.
c
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provided the desired reactivity in tests with 1-decyne (Table 1). The applicability of these features was first demonstrated through
The relative populations of 1–5 are most easily attained by integra- simple cross-coupling of (E)-PhCHQCHAlCl2 to PhBr (Table 2).
tion of the singlets in the 2H{1H} decoupled NMR spectrum of the Dichlorovinylalanes are rather rare, but synthetically useful, species
crude, D2O quenched, reaction mixtures. This simple mechanistic mentioned only in passing in the literature.20
technique does not seem to have been greatly used before to screen
hydroaluminations (see ESI† for details).
Conditions similar to our related DABAL-Me3 coupling proved
effective.21 In particular, addition of DABCO to form the DABAL-
The alane alone gave chemoselective hydroalumination but its (vinyl)Cl2 reagent in situ led to a maximised yield of the desired
rate was unacceptable (Run 1). Titanocene dichloride was active but (E)-product. Satisfyingly, the presence of neither the zirconium
poorly regioselective (Run 2). Simple zirconocene dichloride inhi- catalyst nor small amounts of 4 (Y = Cl) inhibit the coupling and
bited conversion providing poorer and variable conversions (Run 3).
Table 3 Scope of the hydroalumination/cross-coupling procedurea
We speculated this was due to the formation of stable dichloroalane
adducts, perhaps related to Cp2Zr(m-H)(m-H2AlCl2)ZrCp2,13 and
planned to disrupt this via use of sterically encumbered metallo-
cenes.14 While Cp2ꢁTiCl2 has been employed in LiAlH4 alkene
hydroaluminations15 its use here had two negative features: firstly,
with HAlCl2ꢀ(THF)2 it gave unclean reactivity generating (Z)-1, 3–5
and hydrogen transfer products; secondly, its literature preparation
and cost are very uninviting.16 As far as we can determine, Cp2ꢁZrCl2
has not been used in alkyne hydroalumination before. However,
this pre-catalyst is highly potent for terminal alkyne HAlCl2 addition
(Runs 5–8), the only significant by-product being some 4, which
shows no reactivity towards electrophiles vs. (E)-1 in subsequent
catalysis.
Run
Catalystb
R1
R2
X
Yieldc (%)
1
2
3
4
5
6
7
8
Zr
Zr
Zr
Ti
Zr
Zr
Zr
Zr
Zr
Ti
Zr
Zr
Ti
Zr
Zr
Ti
Ti
Zr
Zr
Zr
Zr
Ti
Zr
Ti
Zr
Zr
Zr
Zr
Zr
C6H13
C8H17
Bui
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Br
Br
Br
Br
I
98
96
88
93d
98
86e
41
75
61f
86
95
96
71
57
91
71
71
94
55
85
87
81
92
65
95
99
95
94
63
But
Ph
Ph
Ph
OTf
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
A
number of practical issues make the use of
BnO(CH2)3
HO(CH2)3
But
Cpꢁ2ZrCl2-HAlCl2ꢀðTHFÞ2 rather attractive: (i) The alane (a non
pyrophoric colourless crystalline solid) is easily prepared on at least
50 g scales (see ESI†) and it can be handled in air for up to 30 min
with o5% decomposition. While this is not as robust as our air-
stable AlMe3 analogue DABAL-Me3, it does allow prompt weighing
of gram quantities in the open laboratory.17 (ii) Cp2ꢁZrCl2 is
commercially available or alternatively easily prepared.18 (iii) Simple
distillation of the alkyne allows low (2 mol%) catalyst loadings and
short reaction times (down to 2 h) to be used. (iv) At 5 mol% the
catalyst system is really rather robust and will often tolerate
unpurified alkynes, variable reaction times (2–16 h) and alternative
use of dioxane as a solvent.19 (iv) Terminal alkynes with more
acidic RCH bonds are also well tolerated (aryl- an ene–ynes).
(v) For more sterically encumbered alkynes (e.g. ArCRCH,
ButCRCH) Cp2ꢁZrCl2 could be replaced by simple titanocene
dichloride without appreciable formation of 3. (vi) No transmetalla-
tion or solvent switch is needed allowing one-pot procedures.
9
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
3,5-Me2Ph
3,5-Me2Ph
3,5-Me2Ph
1-Naphthyl
1-Naphthyl
2-Naphthyl
3-MeOPh
4-CF3Ph
4-CF3Ph
3-(NO2)Ph
4-(CO2Me)Ph
4-MePh
2-MePh
2-MePh
3-MePh
3-MePh
Mesityl
4-(CN)Ph
3-(CN)Ph
(E)-CHQCHPh
C6H13
Ph
But
C6H13
C6H13
But
But
C6H13
C6H13
C6H13
C6H13
But
C6H13
But
C6H13
C6H13
C6H13
C6H13
C6H13
30
Zr
Ph
Br
68
Table 2 Optimisation of the hydroalumination/cross-coupling procedurea
31
32
33
34
35
Zr
Zr
Zr
Zr
Zr
C6H13
C6H13
C6H13
C6H13
C6H13
3-Pyridyl
Br
Br
Br
Br
Br
63f
94g
72
90
78
6-Quinoyl
2-Thiophenyl
3-Thiophenyl
2-Furyl
Hydroalumination catalystb
Additivec
Yieldd (%)
36
Zr
C6H13
Br
77
Run
1
2
3
Cp2TiCl2 (5 mol%)
Cp2TiCl2 (5 mol%)
Cpꢁ2ZrCl2 (5 mol%)
None
DABCO
None
75
94e
81
a
R2X (2.0 mmol) in THF (4 mL) for hydroalumination; cross-coupling
b
components added in additional THF (4 mL). Zr is Cpꢁ2ZrCl2; Ti is
Cp2TiCl2. Isolated yields. 41% yield was attained with the Zr
catalyst. Use of the Ti catalyst led to a mixture of C(1) and C(2)
4
Cpꢁ2ZrCl2 (5 mol%)
DABCO
94e
c
d
e
a
Chemistry of Scheme 1 (R = Ph, Y = Cl) using phenylacetylene
f
b
products. Additional HAlCl2 used (1.1 equiv.) in hydroalumination.
(2.00 mmol) in THF (4 mL) at 80 1C. Cp is Z-C5H5, Cp* is Z-C5Me5.
g
c
d
Additional HAlCl2 used (1.1 equiv.) in hydroalumination and InCl3
0.7 equiv. based on phenylacetylene. By GC (FactorFour column)
e
co-catalysis (14–21 mol%) in cross-coupling.
tridecane internal standard. Isolated yield.
c
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no other co-promoter was needed. Extending this procedure raises
three key questions: firstly, how general is the cross-coupling
procedure with respect to the alkyne and electrophile? Secondly, is
Pd-catalysed cross-coupling limited to the proprietary X-phos ligand?
Finally, how does this procedure ‘measure up’ against established
DIBAL-H based processes? The generality of the two-stage process is
demonstrated in Table 3. The required vinyl alanes were attained
from precursor alkynes using Cpꢁ2ZrCl2 (5 mol%) with reaction
times of 2–16 h; for hindered alkynes Cp2TiCl2 (5 mol%, 2 h) was
sometimes used. In reaction of HO(CH2)3CRCH extra equivalents
of HAlCl2ꢀ(THF)2 was used together with InCl3 co-catalysis.22 Similar
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and alcohol functional groups in the alkyne were tolerated attempts
to use alkynes containing ester or cyano functions led to their
reduction or catalyst inactivation respectively. (ii) Esters were
tolerated in the coupling partner but nitro groups were partially
attacked. In coupling of pyridyl-type heterocycles additional excesses
of alane and InCl3 co-catalysis were required to attain acceptable
yields. Finally, if unpurified alkynes were used significant amounts
of d0-alkene were occasionally detected at long reaction times due
hydrogen transfer. However, this did not affect the overall efficiency
of the process as excesses of (E)-1 are still present. To answer the
question of the efficacy of the process described here against
literature precedent direct comparison against standard DIBAL-H
based hydroalumination conditions was made using a common
Pd-coupling catalyst (see ESI†). In each case investigated the
dichloroalane route was quicker and higher yielding. In other
trials we could also replace X-phos with the non-proprietary, and
industrially used Ata-phos23 ligand, with some success (Scheme 2).
Overall, a non pyrophoric alane (that can be handled briefly
in air) providing >40 : 1 reactive (E)-C(1)-organoalanes from low
loadings of commercial catalysts with minimal by-products
constitutes useful methodology. It has wide range, high potential
for use on large scales, compares well to current systems and can be
expected to find use in both cross-coupling and other subsequent
metal-catalysed processes using such vinyl alanes as nucleophiles.
The latter are currently being actively investigated by us.
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˜
´
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stored under inert atmospheres using standard Schlenk techniques.
´ˇ
´
18 J. Hiller, U. Thewalt, M. Polasek, L. Petrusova, V. Varga, P. Sedmera
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85%); toluene (67%/significant 2 11% and reproducibility issues).
Refluxing MTBE and Et2O gave very poor reactions.
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¨
J. Kosters, M. Layh, M. Rohling, A. Vinogradov, E.-U. Wu¨rthwein and
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.